# Estimation of Protein-Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations

Source: [Estimation of Protein-Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations](<https://www.sota2.com/research/paper/68fa3aef1e209131ce8cea3b>)

Collection index: [llms.txt](<https://www.sota2.com/research/llms.txt>)

Data updated: 2025-10-25T00:19:44.449Z

Authors: Steffen Wolf, Marta Amaral, Maryse Lowinski, Francois Vall\\'ee, Djordje Musil, J\\"orn G\\"uldenhaupt, Matthias K. Dreyer, J\\"org Bomke, Matthias Frech, J\\"urgen Schlitter, Klaus Gerwert

Published: 2019-07-25T10:57:59.000Z

## Abstract

We here report on non-equilibrium targeted Molecular Dynamics simulations as tool for the estimation of protein-ligand unbinding kinetics. Correlating simulations with experimental data from SPR kinetics measurements and X-ray crystallography on two small molecule compound libraries bound to the N-terminal domain of the chaperone Hsp90, we show that the mean non-equilibrium work computed in an ensemble of trajectories of enforced ligand unbinding is a promising predictor for ligand unbinding rates. We furthermore investigate the molecular basis determining unbinding rates within the compound libraries. We propose ligand conformational changes and protein-ligand nonbonded interactions to impact on unbinding rates. Ligands may remain longer at the protein if they exhibit strong electrostatic and/or van der Waals interactions with the target. In the case of ligands with rigid chemical scaffold that exhibit longer residence times however, transient electrostatic interactions with the protein appear to facilitate unbinding. Our results imply that understanding the unbinding pathway and the protein-ligand interactions along this path is crucial for the prediction of small molecule ligands with defined unbinding

## Recorded benchmark results

A research result applies to its stated dataset, split, metric and evaluation configuration. Compare like-for-like settings, preserve the metric's unit and direction, and distinguish paper-reported results from independent reproduction. The best result recorded here is not a claim of exhaustive, current global coverage.

## Original sources and implementation

[Original paper](<https://arxiv.org/abs/1907.10963>)

[PDF](<https://arxiv.org/pdf/1907.10963.pdf>)